This application is a 371 of PCT/EP99/09333 filed Dec. 1, 1999.
The invention relates to chroman derivatives of the formula I 
in which
R1 is acyl having 1-6 C atoms, xe2x80x94COxe2x80x94R5 or an amino protective group,
R2 is H or alkyl having 1-6 C atoms,
R3, R4 in each case independently of one another are H, alkyl having 1-6 C atoms, CN, Hal or COOR2.
R5 is phenyl which is unsubstituted or mono- or disubstituted by alkyl having 1-6 C atoms, OR2 or Hal,
X is H,H or O,
Hal is F, Cl, Br or I,
and their salts.
The invention also relates to the optically active forms, the racemates, the enantiomers and also the hydrates and solvates, e.g. alcoholates, of these compounds.
Similar compounds are disclosed in EP 0 707 007.
The invention was based on the object of finding novel compounds which can be used, in particular, as intermediates in the synthesis of medicaments.
It has been found that the compounds of the formula I and their salts are important intermediates for the preparation of medicaments, in particular of those which show, for example, actions on the central nervous system.
The invention relates to the chroman derivatives of the formula I and their salts.
Above and below, the radicals R1, R2, R3, R4, R5 and X have the meanings indicated in the formulae I and II, if not expressly stated otherwise.
In the above formulae, alkyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms. Alkyl is preferably methyl or ethyl, furthermore propyl, isopropyl, in addition also butyl, isobutyl, sec-butyl or tert-butyl. Acyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms Acyl is in particular acetyl, propionyl or butyryl.
R2 is preferably H, in addition also methyl, ethyl or is propyl.
R3 and R1 are preferably H.
R5 is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl. The radical R1 is acyl, xe2x80x94COxe2x80x94R5 or else an amino protective group which is known per se; acetyl is particularly preferred.
The expression xe2x80x9camino protective groupxe2x80x9d is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise uncritical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the widest sense in connection with the present process and the present compounds. It includes acyl groups derived from, aliphatic, araliphacic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl: aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (carbobenzoxycarbonyl, also called 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxy-carbonyl); arylsulfonyl such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protective groups are BOC and Mtr, an addition CBZ or FMOC.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I according to claim 1 and also of their salts, in which X is O, characterized in chat a compound of the formula II 
in which R1, R2, R3, R4 have the meanings indicated in claim 1 and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst.
The invention also relates to a process for the preparation of chroman derivatives of the formula I according to claim 1 and also of their salts, in which X is H,H, characterized in that a compound of the formula II 
in which R1, R2, R3, R4 have the meanings indicated in claim 1 and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst, and then reduced in the customary manner.
In particular, it has been found that (2-acetylaminomethyl)chromen-4-one can be hydrogenated using various enantiomerically pure rhodium-diphosphane complexes to give enantiomerically enriched (2-acetylaminomethyl)chroman-4-one.
The invention also relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the enantiomerically enriched catalyst is a transition metal complex.
Particularly preferably, the catalyst is a transition metal complex comprising a metal selected from the group rhodium, iridium, ruthenium and palladium.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the catalyst is a transition metal complex in which the transition metal is complexed with a chiral diphosphane ligand.
The ligands below may be mentioned by way of example: 
Depending on the choice of the (R) or (S) enantiomer of the ligand in The catalyst, the (R) or (S) enantiomer is obtained in an excess.
Precursors used for the chiral ligands are compounds such as, for example, Rh(COD)2OTf (rhodium-cyclooctadiene triflate), [Rh(COD)Cl]2, Rh(COD)2BF4, [Ir(COD)Cl]2, Ir(COD)2BF4 or [Ru(COD)Cl2]x.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), mainly under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds.
The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is O is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as, for example, methanol or ethanol.
Suitable inert solvents are furthermore, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, and optionally also mixtures of the solvents mentioned with one another or mixtures with water.
The reaction time of the enantioselective hydrogenation, depending on the conditions used, is between a few minutes and 14 days; the reaction temperature is between 0 and 150xc2x0, normally between 20 and 130xc2x0.
Customarily, the catalyst/substrate ratio is between 1:2000 and 1:50, particularly preferably 1:1000 and 1:100. The reaction time is then, for example, between 3 and 20 hours. The hydrogenation is carried out under 1-200 bar of hydrogen, preferably at 3-100 bar.
The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is H,H is carried out according t o the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as methanol or ethanol, such as described above, followed by a conversion of the 4-oxo group into a methylene group according to known conditions. The reduction is preferably carried out using hydrogen gas under transition metal catalysis (for example by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol).
The conversion of compounds of the formula I in which R3, R4 is COOalkyl into compound s of the formula I in which R3, R4 is COOH is carried out, for example, using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100xc2x0.
The removal of a radical R1 from a compound of the formula I is carried outxe2x80x94depending on the protective group usedxe2x80x94for example using strong acids, expediently using TFA (trifoluoroacetic acid) or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures are expediently between approximately 0 and approximately 50xc2x0; the reaction is preferably carried out between 15 and 30xc2x0.
The BOC group is preferably removed using TFA in dichloromethane or using approximately 3 to 5 N hydrochloric acid in dioxane at 15-30xc2x0. The removal of the acetyl group is carried out according to customary methods (P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994).
Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100xc2x0 and pressures between approximately 1 and 200 bar, preferably at 20-30xc2x0 and 1-10 bar.
A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are particularly those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, using bases (e.g. sodium or potassium hydroxide or carbonate), or into the corresponding ammonium salts.
The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments. Appropriate medicaments are described, for example, in EP 0 707 007.
The invention accordingly relates in particular to the use of the compounds of the formula I according to claim 1 in the synthesis of
(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman and its salts, characterized in that
a) a compound of the formula II 
xe2x80x83in which
R1 has the meaning indicated in claim 1,
R2, R3 and R4 are H and X is O,
is hydrogenated with the aid of an enantiomerically enriched catalyst,
b) in that, from the enantiomerically enriched mixture of the (R) and (S) compounds of the formula I thus obtained, in which
R1 has the meaning indicated in claim 1,
R2, R3 and R4 are H and X is O.
the enantiomerically pure (R) compound of the formula I, in which
R1 has the meaning indicated in claim 1,
R2, R3 and R4 are H and X is O,
is obtained by crystallization, in that
c) the enantiomerically pure (R) compound of the formula I, in which
R1 has the meaning indicated in claim 1,
R2, R3 and R4 are H and X is O,
is then reduced in the customary manner, in that
d) the radical R1 in which
R1 has the meaning indicated in claim 1,
R2, R3 and R4 are H and X is H,H,
is removed from the (R) compound of the formula I thus obtained, in that
e) the (R)-(chroman-2-ylmethyl)amine thus obtained is converted into its acid addition salt and this is reacted in a known manner to give (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman and, if appropriate, converted into its acid addition salt, where the recovery of the (R) enantiomer can also be carried out by crystallization from the enantiomerically enriched (R,S) mixture after stage c) or after stage d).
The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments which show actions on the central nervous system.
Above and below, all temperatures are indicated in xc2x0C. In the following examples, xe2x80x9ccustomary working upxe2x80x9d means: if necessary, water is added, the mixture is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Rf values on silica gel.